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Module 2: MSK > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What are two critical mediator pathways of inflammatory conditions?

A
  1. Nuclear Factor Kappa B (NF-kB)
  2. Arachidonic Acid Cascade
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2
Q

What are stimuli and target genes for NF-kB?

A
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3
Q

What is the arachidonic acid cascade?

A

Arachidonic acid is cleaved from membrane phospholipids by Phospholipase A2

It is used to in the lipoxygenase pathway to make leukotrienes and the Cyco-oxygenase pathway to make prostaglandins, prostacyclin, and thromboxane A2

Pathways are determined by the tissue/cell

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4
Q

What pathway do NSAIDs inhibit?

A

COX-1 and COX-2 pathways

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5
Q

What are characteristics of the COX-1 pathway?

A
  • Constitutively expressed in many tissues
  • generates thromboxanes
  • Generates low levels of prostaglandins
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6
Q

What are characteristics of the COX-2 pathway?

A
  • Most responsive for inflammatory response
  • Inducible form of enzyme; expressed in high levels after induction by inflammatory mediators
  • Generates high levels of prostaglandins and thromboxanes

Functions:
local inflammation
wound healing
resistance to infection

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7
Q

What are functions of prostaglandins?

A
  • protective (i.e. gastric mucosa)
  • maintains local blood flow / vasodilation (i.e. kidney)
  • platelet aggregation
  • uterine contraction
  • muscle growth
  • modulation of synaptic transmission
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8
Q

Thromboxanes are dependent on which enzyme for their synthesis?

A

COX-1

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9
Q

What are some non-selective COX inhibitors?

A

aspirin (irreversible)

ibuprofen

naproxen

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10
Q

What are some toxic side effects of NSAIDs?

A

- Gastrointestinal tract

- Renal effects

- Hypertension

- Impaired hemostasis

- Allergic hypersensitivity rxns

- CNS toxicity

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11
Q

What are some GI side effects of NSAIDs?

A

Dyspepsia

Ulcers

Inflammation

Gastric erosion, hemorrhage

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12
Q

What are some renal side effects of NSAIDs?

A

Glomerular filtration rate reduced

Edema

Necrosis

Nephritis

Hyperkalemia

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13
Q

What are some pharmacokinetic interactions of NSAIDs that increase NSAID toxicity?

A

potentiation of drugs bound to plasma proteins
(warfarin, phenytoin, sulfonylureas, methotrexate)

Inhibition of drug metabolism
(phenylbutazone)

Inhibition of acid transport in kidney
(by probenecid)

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14
Q

What are some pharmacodynamic intereactions of NSAIDs that increase their toxicity?

A

Increased risk of bleeding after alcohol

Reduced effects of anti-hypertensive agents
(beta-adrenergic antagonists, ACE inhib., diuretics)

Inhibition of renal clearance of Lithium

Sudden hyperkalemia with K+-sparing diuretics

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15
Q

What are the half lives of NSAIDs?

A

Short half-life (< 6 hr)
aspirin
ibuprofen (Motrin, Advil)
indomethacin

Long half-life (> 6 hr)
naproxen (Aleve)
salicylate
phenylbutazone

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16
Q

What are COX-2 selective inhibitors?

A

celecoxib (celebrex)

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17
Q

What are other analgesic/anti-inflammatory (non-NSAID) agents?

A

Glucocorticoids

Acetaminophen (tylenol)

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18
Q

What are characteristics of glucocorticoids?

A
  • effective anti-inflammatory agents
  • inhibit Phospholipase A2, reduce arachidonic acid levels
  • inhibit production of inflammatory cytokines (IL-1, TNFalpha, IFNgamma)
  • inhibit NF-kB signaling and thus inhibit COX-2 inhibition
  • significant side effects limit use
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19
Q

What are characteristics of aceteminophen?

A
  • analgesic, antipyretic agent
  • less effective anti-inflammatory agent
  • a weak inhibitor of COX-1 and COX-2
  • exact mechanism unknown
  • drug of choice for fever, headache in infants
20
Q

What about COX-2 specific inhibitors has led to their removal from the market?

A

They have increased cardiovascular risk, thought to be because they alter the balance between thromboxanes and prostacyclins, by inhibiting pathways leading to prostacyclin synthesis

21
Q

What are possible drug treatment options for arthritic conditions?

A

Relief of symptoms:
NSAIDs

Disease modifying anti-rheumatic drugs (DMARDs)

22
Q

What are the different categories of DMARDs?

A

Synthetic Drugs:

Immunosuppresant agents

Biologics:

TNFalpha Blockers

IL-6 mAb

IL-1 Receptor antagonist

Immune Modulators

23
Q

What are some notable Immunosuppressant DMARDs?

A

Methotrexate
Leflunomide

24
Q

What are some notable TNFalpha blockers?

A

etanercept
infliximab

25
Q

What are some notable IL-1 receptor antagonists?

A

anakinra

26
Q

What are some notable immune modulator DMARDs?

A

abatacept
rituximab

27
Q

What are characteristics of methotrexate?

A
  • Immunesuppressant:
    dihydrofolate reductase inhibitor
  • Effectiveness is dose-related
  • Slow onset of effects
  • Side effects:
    anorexia, vomiting, abdominal cramps
    mucosal ulcers, hepatotoxicity
    mild leucopenia, thrombocytopenia
  • may be used in combination with other disease modifying drugs
28
Q

What are characteristics of leflunomide?

A
  • Inhibits pyrimidine synthesis by inhibiting dihydroorate dehydrogenase
  • reduces lymphocyte proliferation
  • potent immunosuppressant
  • pro-drug (active metabolite)
  • long half-life
  • long-term effectiveness/toxicity unkown
  • inhibits CYP2C9
  • Adverse Effects:
    hepatotoxicity
    hypertension
    teratogenic
    may cause fetal death
29
Q

What are characteristics of etanercept?

A

TNF-alpha blocker

  • a chimeric TNF receptor, blocks binding of TNF-alpha
  • reduces joint swelling
  • combined with methotrexate
  • long-term effectiveness/toxicity unknown
  • increased risk of latent TB activation
30
Q

What are characteristics of Infliximab?

A

TNF-alpha antibody - blocks stimulation by TNF-alpha

  • combined with methotrexate
  • long-term effectiveness/toxicity unknown
31
Q

What is the target for rituximab?

A

CD20+ B cells

  • rituximab prevents development and proliferation of B cells
32
Q

What are the two types of cholinesterases?

A

Acetylcholinesterase

Plasma cholinesterase

33
Q

What is a cholinesterase inhibitor?

A

Molecules that look like ACh to AChE, ultimately blocking AChE’s ability to cleave ACh

34
Q

What are the types of cholinesterase inhibitors?

A

Quarternary alcohols, Carbamates:
Clinical use; choice depends on desired site and duration of action

Organophosphates:
Slowly reversible or irreversible: few clinical uses (except glaucoma)
Found in insecticides and nerve agents

35
Q

What are medical uses of anticholinesterases?

A

Myasthenia Gravis

Anesthesia

Alzheimer’s Disease

Glaucoma

Emergency Medicine

Bladder control

Dry mouth

36
Q

What’s the difference between carbamates and organophosphates that determines their reversibility?

A

Both act as intermediates of the AChE rxn, blocking the rxn

Carbamate can be dislodged by H2O as a nucleophile

Organophosphates need nucleophiles stronger than H2O initially, then undergo aging which makes them completely irreversible and new AChE must be produced

37
Q

What is Edrophonium?

A

Used for diagnosis of Mysathenia Gravis
and reversal of neuromuscular blockade by non-depolarizing muscle relaxants

Bioavailability: IV or IM injectable
Active for ~30min

Metabolism: renal

Adverse effects minimal due to fast elimination

38
Q

What is Pyridostigmine?

A

Myasthenia Gravis treatment
(Also, organophosphate poisoning prophylaxis)

Bioavailability: oral treatment
Peak after 30min
active ~4 hrs

Metabolism: renal

Adverse effects:
GI symptoms of nausea, vomiting or diarrhea
sweating and flushing
increased salvation
tearing and constricted pupils
bronchial secretions

39
Q

What is Donezipil?

A

Alzheimer’s treatment

Bioavailability: oral treatment
Peak concentration after 4hrs
accumulates in brain 2x plasma levels
active ~ 80hr

Extreme half life requires increasing dose slowly, including a 1 week titration, to avoid adverse effects

Metabolism: renal

40
Q

What is cholinergic crisis?

A

Can occur by overdose of anti-AChE drugs:

SLUDS: Salivation, lacrimation, urination, defication, sweating

  • Miosis
  • profuse secretion
  • bronchial constriction
  • defecation/urination
  • bradycardia
  • hypotension
  • muscle twitches
  • convulsions
  • respiratory failure
41
Q

What is Physostigmine?

A

Used for Emergency medical reversal of anticholinergics or antihistamines:
Anticholinergics = atropine, scopolamine
antihistamines = diphenhydramine, dimethylhydrinate
“recreational” Jimson weed

Bioavailability: oral or injectable
peak concentration ~10-30min
Transdermal patch for 24hr exposure

Metabolism: liver metabolism, renal elimination

Adverse effects: S.L.U.D.S.

NOTE: also used to treat xerstoma (dry mouth)

42
Q

What is the intermediate syndrome of organophosphate poisoning?

A

May occur for up to 1 week after exposure

modifications in function of nicotinic receptors

Symptoms do not respond to:
atropine
2-PAM

Symptoms resolve on own in week or two

Treatment is supportive (respirator)

43
Q

What is Organophosphate-induced delayed polyneuropathy (OPIDP)?

A

Symptoms:
muscle weakness
headaches
psyciatric problems
memory problems

Cause not established; likely chronic exposure to OPs

No established pharmaceutical therapy

44
Q

What is pralidoxime (2-PAM)?

A

hydroxylamine derivative with a cationic head that is able to regernate AChE active site after organophosphate exposure

Not indicated for carbamate overdose

45
Q

What is used to treat organophosphate poisoning?

A

Remove all sources of agent (clothes, etc)

atropine - immediately to stop secretions

pralidoxime (2-PAM) - immediately to regenerate enzyme

diazepam to reduce convulsions

Supportive measures (i.e. respirator)

46
Q

What is the current protection to organophosphate poisoning?

A

Prophylactic opportunity with pyridostigmine:

Inhibit a fraction of AChE with spontaneously reversible anti-AChE before exposure

This is possible b/c poisoning effects appear after > 50% enzyme is inhibited

Module 2: MSK (11 decks)

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